There is abundant evidence that autoantibodies (autoAbs) are generated through somatic hypermutation and that tolerance of B cells that acquire self-reactivity through this process is impaired in systemic lupus erythematosus (SLE). Although recent studies have provided considerable insights into the participants and cellular dynamics in germinal center (GC) reactions where somatic hypermutation (SHM) takes place, there has been little progress in understanding the mechanisms for maintaining tolerance of newly generated self- reactive B cells, largely because of the absence of an appropriate model. We, in collaboration with other investigators, have recently used a novel 32a-macroself antigen (Ag) transgenic (Tg) system to show that Fas- deficient mice are defective in censoring B cells that have acquired autoreactivity to a surface-bound Ag. This model, however, utilizes an artificial Ag with characteristics that differ substantially from the purported autoAgs in SLE. To address these limitations, we have formulated a new B cell receptor Tg model that will allow replacement of an innocuous antigen-receptor with a DNA-binding receptor in B cells undergoing class switch recombination (CSR)/SHM, and seek to develop this model and use it to investigate post-SHM tolerance mechanisms in normal and autoimmune mice. To accomplish this, three aims are proposed that will: 1) generate the FLEx-autoAb model system, 2) characterize tolerance of post-CSR/SHM B cells in non- autoimmune mice, and 3) characterize tolerance of post-CSR/SHM in lupus-prone B6-Faslpr mice. This novel approach has the potential for significantly improving our ability to study tolerance of B cells that acquire autoreactivity in the periphery, to generate new and important insights into this process, and to substantially advance this area of investigation, which is highly relevant to SLE and other autoAb-mediated diseases. PUBLIC HEALTH RELEVANCE: Defective tolerance of B cells to self is considered to be one of the major causes of systemic lupus erythematosus (SLE) responsible for the production of harmful autoantibodies;yet many aspects of this process remain poorly understood particularly tolerance mechanisms that keep in check B cells that acquire self-reactivity during somatic hypermutation. Currently none of the existing animal models are able to directly study mature B cells that acquire autoreactivity to self-antigens commonly targeted in SLE. To address this issue, we proposed to generate a new and more relevant model, called FLEx-autoAb, using a novel approach.